The overall aim of the project is to determine whether a missense mutation in the ATM gene (mutated in ataxia telengiectasia) predisposes heterozygous carriers to cancer and to investigate the mechanism of predisposition. A "knock-in" mouse model will be employed to address this question. The issue of whether carriers of the defective human ATM gene are prone to cancer, especially breast cancer, is a vexed one with epidemiological data supporting an increased cancer risk but ATM mutation data failing to support the population studies. However, it is now evident that when missense mutations are focused upon the association with cancer susceptibility becomes significant. Our recent observations that heterozygotes for a "knock-in" Atm mutant mouse (7666del9, Atm-SRI) are susceptible to cancer provides further support for the results in humans and describes the first mouse model for cancer proneness in carriers of a defective Atm gene. [unreadable] [unreadable] Specific Aims [unreadable] Aim 1 Generation of a "knock-in" mutant mouse harboring a missense mutation in Atm (S2602C) [unreadable] Aim 2 Investigation of predisposition to cancer development in mice heterozygous for Atm (S2602C) [unreadable] Aim 3 Investigation of the mechanism of dominant interference by the Atm (S2602C) missense mutation [unreadable] To address the issue of cancer predisposition in A-T heterozygotes, a mouse model expressing an Atm missense mutation (corresponding to S2592C already detected in this gene in a patient with breast cancer and shown to interfere with ATM kinase) will be generated and cancer development monitored in carriers of the defective gene. This will be monitored in the first instance in animals not exposed to exogenous agents and subsequently in animals exposed to low doses of radiation. The mechanism by which the mutant form of Atm causes cancer will be investigated at the molecular level in cells stably transfected with Atm cDNA. This model system is expected to add further substance to the hypothesis that ATM missense mutations are the changes in ATM responsible for at least some of the increased cancer risk in gene carriers. [unreadable] [unreadable]